1. Technical Field
The invention relates to the field of biomedicine and specifically methods useful for cancer therapy. In particular, embodiments of the invention relate to methods for specific CTL immunotherapeutic strategies for cancer including the use of genetically-modified T lymphocytes expressing chimeric immunoreceptors in the treatment of human brain tumors and other cancers.
2. Description of the Background Art
Tumor-specific T cell based immunotherapies have been investigated for anti-tumor treatment, however the T cells suffer from the problem of not surviving and remaining active in vivo for a long enough period. Often, adoptively transferred T cells do not have the desired potency and duration of tumor cell killing. Therefore, there is a need in the art for tumor-specific cancer therapies with longer term anti-tumor functioning.
Cancer-directed immunotherapies traditionally focus on eliciting CD8+ CTL responses. However, stimulation of CD4+ T cell (helper) responses also is important to successful immunotherapy against cancer. CD4+ T cells can influence natural tumor-specific CTL responses directly or indirectly, through conditioning of professional antigen presenting cells via CD40-CD40L, and through the production of cytokines such as IL2 and IFN-γ. The cytocidal effector mechanisms used by CD4+ T cells are mediated either through release of cytokines that activate death receptors on the tumor cell surface, or through direct cell contact where Fas/FasL, TNF-related apoptosis-inducing ligand (TRAIL), or granzyme-perforin dependent pathways mediate tumor cell apoptosis. These helper cells can augment the early clonal expansion and generation of primary CD8+ CTL effectors, and also may affect both the generation and the expansion of functional memory CD8+ T cells.
Full activation of natural CD4+ T cells requires both an antigen-specific signal through engagement of the T cell receptor/CD3 complex with appropriate peptide/MHC class II complexes and costimulatory signals. These costimulatory signals usually are delivered by ligands that are selectively expressed on specialized antigen presenting cells. T cell costimulation is thought to help maintain tolerance to normal self-antigens expressed by tissues that do not deliver this secondary signal. Because most tumor cells, similar to normal tissues, do not express MHC class II or costimulatory molecules, it stands to reason that they also do not normally promote CD4+ T cell stimulation directly. This theory is supported by several studies that have demonstrated enhanced T cell mediated anti-tumor immunity by vaccination with tumor cells that were transfected with the costimulatory ligand B7-1.
While altering tumor cell expression of costimulatory molecules is one way to help drive T cell activation, alternative strategies would be very desirable, particularly strategies which involve allowing the T cell to receive and act on costimulatory signals without the need for actual costimulatory ligand(s).